It is widely accepted that susceptibility to insulin dependent diabetes (IDD) is genetically determined by one or more genes at one or more diabetic loci linked to HLA. Genetic heterogeneity of IDD is suspected by some but the support for this concept has been scanty and in many cases unconfirmed. We propose in this application to evaluate possible evidence of genetic heterogeneity within IDD by studying a large number of IDD families ascertained a) for the presence of multiple affected sibs (multisib or MS families) and b) in a way as random as possible (R families). multisib affected families and randomly ascertained families will be typed for HLA/A, B, and DR, and for C2, C4, and the Bf system. Approximately one-half of multisib families and nearly all random families have been completely typed for HLA A and B and, to a large extent, for HLA DR. The extensive characterization of HLA supratypes using two polymorphic systems in man (HLA and C4) may identify new aspects of the association and linkage of IDD within the HLA region. A rare C4 variant (C4B4) has already been found with high frequency in IDD; this variant may be the same found in rheumatoid arthritis, another DR4 related disease. The rare C4 types may help to further characterize the IDD supratypes and help our understanding of the pathogenesis of IDD, including interaction between genetic and environmental (viral?) factors. Other intriguing relationships between disease, including IDD, and complement types are discussed in this proposal. We also propose to perform primed lymphocyte typing with T cell clones (PLT) in at least 10 IDD families with each of the following HLA proband genotypes: high risk (DR3/4, Dr3/3, Dr4/4) and low risk (DR2/x, DRx/x). It is postulated that a finer dissection of the HLA region with PLT will characterize further the IDD supratypes and may uncover additional determinants (other than DR3 and DR4) which are strongly associated with IDD or may themselves be the IDD susceptibility factors. Genetic analyses of the family data will include association, segregation, and linkage analyses. The latter will be performed with improved computer programs developed by Dr. Newton Morton.